569
Shatha Dmour
1, Ala’a Al-Maaitah
1, Tunc Eren
2, Ozgur Ekinci
2, Orhan Alimoglu
2Abstract
Objectives: Papillary thyroid cancer (PTC) is the most common endocrine malignancy and the most common genetic anomaly with PTC is the BRAF V600E mutation. This mutation is linked to many clinical and pathological features and may have a diagnostic and therapeutic role especially in the era of targeted therapy. The aim of this study is to review the prevalence of BRAF V600E mutation in PTC, its distribution according to the histological subtype and geographic area and its association with the age of patients, gender, subtype and recurrence of tumors.
Methods: The Pubmed database was searched to look for articles about BRAF mutation in PTC. Outcomes of interest included prevalence, age, gender, country, subtype and recurrence.
Results: The prevalence of BRAF V600E mutation in PTC was 47%, with noticeably higher prevalence in the eastern countries. The prevalence of BRAF V600E was also higher in the tall and classic subtypes and could be associated with worse prognosis and higher risk of recurrence.
Conclusions: The BRAF mutation, which is more prevalent in the eastern countries, is determined to be an important molecular marker for PTC.
Key words: Papillary thyroid cancer, BRAF mutation, prevalence
1 The University of Jordan, School of Medicine, Department of Surgery
2 Istanbul Medeniyet University, School of Medicine, Department of General Surgery, Istanbul, Turkey
Corresponding author: Orhan Alimoglu, Istanbul Medeniyet University, School of Medicine Department of General Surgery Istanbul, Turkey e_mail: orhan.alimoglu@medeniyet.edu.tr
Prevalence of BRAF Mutation in Papillary Thyroid Cancer
REVIEW/DERLEME
Özet
Amaç: Papiller tiroid kanseri (PTK) en sık endokrin malignite olup PTK ile ilişkili en sık genetik anomali BRAF V600E
mutasyonudur. Bu mutasyon birçok klinik ve patolojik özellikler ile ilintilidir ve özellikle hedefe yönelik tedavi çağında tanısal ve tedavisel rolü olabilir. Bu çalışmanın amacı, BRAF V600E mutasyonunun PTK için prevalansını, histolojik varyant ve coğrafi bölgeye göre dağılımını, hasta yaşı, cinsi, tümör alt tipi ve nüksü ile olan ilişkisini değerlendirmektir.
Yöntemler: PubMed veritabanında PTK için BRAF mutasyonu ile ilgili makaleler taranarak prevalans, yaş, cins, ülke, alt tip ve nüksü içeren veriler değerlendirildi.
Bulgular: Doğu ülkelerinde belirgin olarak daha yüksek olmak üzere PTK için BRAF V600E mutasyonunun prevalansı %47 saptandı. Daha kötü prognoz ve daha yüksek nüks riski ile ilişkili olabilecek şekilde BRAV V600E prevalansı, tall hücre varyantı ve klasik varyantta daha yüksekti.
Sonuç: Doğu ülkelerinde PTK için daha yüksek prevalansa sahip olduğu saptanan BRAF mutasyonunun, bu malignite için önemli bir moleküler belirteç olduğu düşünülmektedir.
Anahtar kelimeler: Papiller tiroid kanseri, BRAF mutasyonu, prevalans
Papiller Tiroid Kanserinde BRAF Mutasyonu Prevalansı
43(4 )2016 www.diclemedj.org 570
INTRODUCTION
Thyroid cancer, with a rapidly increasing
incidence, is the most common endocrine
malignancy, which accounts for 1% of all
cancers [1]. Papillary thyroid cancer (PTC)
accounts for around 85% of all thyroid
malignancies [2]. Although it has a favorable
prognosis with an average 10-year survival rate
of more than 95%, approximately 10% of
patients eventually die mainly because of
disease recurrence [3].
Recent advances in molecular medicine have
led to significant insights into the genetic basis
of thyroid tumorigenesis, and a large number of
genetic mutations were found to be involved in
the carcinogenesis of PTC, like; BRAF, RAS, RET,
PAX8 genes mutations and others, which may
carry diagnostic, prognostic and therapeutic
roles [4].
BRAF gene is located on chromosome 7, and it
encodes the BRAF protein, which is involved in
a pathway that controls and regulates many
cellular processes, like; cellular proliferation,
differentiation and apoptosis. Mutations in this
gene predispose the patients to different
diseases and malignancies, and PTC is a
well-known example, in which BRAF mutations are
the most commonly observed mutations. The
most common mutational hotspot is BRAF
V600E, which creates a constitutively active
BRAF kinase that has been proven to be an
oncogene in human cancer [5-7].
This mutation has been the subject of intensive
investigations because of its specificity for PTC.
It is not frequently seen in follicular, Hurthle
cell,
and
medullary
carcinomas,
and
importantly, BRAF mutation is not present in
benign tumors [8].
In addition to that, this mutation represents a
valuable
marker
that
could
be
used
preoperatively to estimate the risk of PTC
recurrence, which may help us to give an
individualized treatment [9,10]. Additionally,
this mutation has been found to confer a worse
prognosis for PTC due to its association with
advanced and more aggressive presentation
and subtypes and decreased response to
radioactive iodine treatment [11].
Many different studies were held worldwide to
study the prevalence of the BRAF mutation in
PTC and its association with the clinical and
pathological features as well as its role in the
diagnosis of thyroid cancer especially if the
FNA and cytology of a nodule yields a result as
"indeterminate" such as in the Bethesda 3, 4
and 5 categories.
We performed this systemic review in order to
review the prevalence of the BRAF mutation in
PTC, its association with the geographic areas
and its relationship to age, gender, subtype and
recurrence.
METHODS
A comprehensive search of the articles
evaluating the prevalence of BRAF-V600E
mutation in PTC was performed. We searched
the PubMed database using the terms: “BRAF”,
“B-RAF”,
“papillary
thyroid
carcinoma”,
“papillary thyroid cancer”, “PTC” in different
combinations to identify relevant publications.
Outcomes of interest were: prevalence, age,
gender,
geographic
area,
subtype
and
recurrence. We initially narrowed our search
based on the titles of the articles followed by
abstracts and finally full-text articles were
reviewed.
The search was limited to human studies. All
articles were written in the English language.
The references of the eligible articles were
checked for relevant studies.
RESULTS
Prevalence of BRAF in PTC
In general, the prevalence of BRAF mutation in
our review was 47.3% (Table 1).
The association between BRAF mutation and
age
43(4 )2016 www.diclemedj.org 571 Table 1: The prevalence of BRAF mutation in PTC in the
current literature
Percentage of BRAF(+) patients Number of
BRAF(+) patients Number of
patients Study
62% 115
185 Gallupini 2016 [37]
63.3% 102
161 Jo 2016 [32]
54.8% 85
155 DeBiase 2014 [38]
76.5% 297
388 Li 2013 [27]
45.7% 845
1849 Xing 2013 [25]
62.6% 72
115 Schulten 2012 [12]
44.6% 437
1060 Basolo 2010 [16]
33.4 % 81
242 Sykrova 2010 [39]
59.4% 60
101 O’Neill, 2010 [40]
48.6% 120
290 Musholt 2010 [41]
40% 40
100 Xing 2009 [42]
51.7% 153
296 Abu baker 2008
[43]
37.3% 38
102 Elisei 2008 [14]
42.8% 214
500 Lupi 2007 [17]
38% 99
260 Fugazzola 2006 [44]
41.7% 28
67 Riesco-Eizaguirre
2006 [18]
37.8% 45
119 Nikiforova 2003
[13]
47.3% 2832
5990 Total
Schulten et al observed that BRAF-negative
patients were 7 years younger than the
positive patients as the mean age of
BRAF-positive patients was around 44 years while the
mean age of BRAF-negatives was around 37
years (p = 0.025) [12]. Nikiforova et al reported
that BRAF mutation was associated with older
age, where they found that the mean age of
BRAF-positive patients was 49 years while the
mean age of BRAF-negative patients was 35
years [13]. Similarly, an Italian study found that
the BRAFV600E mutation was significantly
more prevalent in older patients, in particular,
in those older than 60 years (p=0.02) [14]. This
result is consistent with the finding that an
advanced age at diagnosis is associated with
poor prognosis [15].
In contrast, Basolo et al observed an inverse
association between age at the time of
diagnosis and BRAF mutation as they found
that this mutation was more common in
younger patients (p=0.006) and the mean age
of BRAF-positive patients was 43 years,
whereas the mean age of BRAF-negative
patients was around 46 years [16].
But many other investigators did not reveal any
significant association between BRAF mutation
and age [17-19-21]. For example, in a large
meta-analyses that included 1168 patients, no
association was determined between age and
the BRAF mutation, and another meta-analysis
that included 3437 patients also supported this
finding [22].
Association between BRAF mutation and
gender
While there was considerable controversy
regarding the relationship between age and the
presence of BRAF mutation, almost all of the
studies stated that there is no significant
association between the presence of BRAF
mutation and gender [13,17,18,20-22]. Except
for few studies like the one of Xu et al, which
reported
significant
difference
in
the
distribution of BRAF mutation between males
and females with higher prevalence of this
mutation in males (p<0.05) [23].
Association between BRAF mutation and the
geographic area
It was found that there is significant geographic
difference in the prevalence of BRAF mutation,
with higher prevalence in the Asian countries
especially Korea which exhibits the highest rate
of BRAF mutation and lower prevalence in the
west [6].
43(4 )2016 www.diclemedj.org 572
42% in Poland [25]. Most of the studies
supported these differences (Table 2).
Table 2: The prevalence of BRAF mutation according to the
countries
Percentage of BRAF(+) patients Number of
patients Country
Study
63.4% 161
Korea Jo 2016 [32]
82.7% 3019
Korea Kim 2015 [24]
54.8% 155
Italy DeBiase 2014 [38]
73.7% 2431
Korea Hong 2014 [40]
67.4% 49
Japan Xing 2013 [25]
45.7% 691
USA Xing 2013 [25]
42% 99
Poland Xing 2013 [25]
39.4% 109
Turkey Kurtulmus 2012
[45]
63% 115
Saudi Arabia Schulten 2012 [12]
33.5% 242
Czech Republic Sykrova 2010 [39]
61.6% 1023
China Guan 2009 [47]
37.3% 102
Italy Elisei 2008 [14]
74.1%
67 Spain
Riesco-Eizaguirre 2006 [18]
38% 260
Italy Fugazzola 2006 [44]
55% 29
Ukraine Xing 2005 [21]
The prevalence of BRAF mutation over time
The prevalence of this mutation has changed
over time. A recent publication revealed an
increase in the prevalence of BRAF mutation in
thyroid malignancies from 62% to 74% in the
last 20 years in Korea. Similarly, in the United
States, the overall prevalence of BRAF
mutations has increased in the last 40 years [6].
The definitive cause behind this is still
unknown, but it may be attributed to the
improvement in the modalities that detect
BRAF mutation and small PTCs.
Association between BRAF mutation and the
PTC subtypes
The prevalence of BRAF V600E mutation differs
according to the histological subtypes of PTC,
with significantly higher prevalence in the
conventional and tall variants, and lower
prevalence in the follicular subtype [26]. To
make things more clear, in a recent study, the
prevalence of BRAF mutation was found to be
88% in the tall variant, 80% in the classical
variant and around 40% in the follicular
variant [27]. Basolo et al stated that, around
80% of tall cell variant PTCs were mutated,
70% of classic variants and only 21% of
follicular variants harbored BRAF mutation
[16]. In other studies, BRAF mutation was
significantly associated with the tall cell variant
(p<0.05), and BRAF-negative tumors were
associated with the follicular variant [13,18].
Similarly, Lupi et al reported that the highest
frequency of BRAF V600E was found in the tall
variant (80%), followed by the conventional
variant (68%), and as expected, significantly
lower frequency (19%) of BRAF V600E
mutations was observed in the follicular
variant [17]. Similarly, Lee et al found that the
prevalence of BRAF mutation was around 80%
in the tall subtype, 60% in the conventional
subtype and 17% in the follicular subtype [20].
Association between BRAF mutation and
recurrence
It was found that there is a significant
association between BRAF mutation and PTC
recurrence, disease recurrence occurred in
32% of BRAF-positive patients but only 7.6% of
BRAF-negative patients developed recurrence
(p=0.02) [18]. In a study that included 2099
patients, BRAF-positive patients were two
times more likely to develop recurrence in the
future (21% vs 11%) [28].
According to Xing et al, the association between
BRAF
mutation
and
disease
recurrence
remained significant even after eliminating the
effect of poor prognostic factors, like; lymph
node metastasis, extra-capsular and advanced
stage (p=0.03). As mentioned before, tall-cell
variant PTCs have a more aggressive course, to
eliminate the effect of this factor some studies
tried to find the association between tumor
recurrence and BRAF mutation using non-tall
cell tumors, and the association remained
significant in the remainder of the tumors
43(4 )2016 www.diclemedj.org 573
mutation is an independent predictor of a more
aggressive disease with worse prognosis [21].
Noticeably, BRAF mutation was more common
in the recurrent tumors (85% of recurrent
tumors harbored BRAF mutation, while only
65% of primary tumors were BRAF-positive)
emphasizing that it is the major mutation in
recurrent PTC [29,30].
DISCUSSION
Thyroid cancer is the most common endocrine
malignancy, it accounts for 1% of all
malignancies, and it was found to be more
common in the Arab world where its incidence
reaches 6% of all malignancies [1,12].
PTC accounts for 85% of all thyroid
malignancies [2]. Although PTC is considered to
be a curable disease with a 10-year-survival
rate of more than 90%, disease recurrence is
quite common, and a minority of patients with
recurrent disease dies. Those patients with
higher risk of recurrence, or when a more
aggressive disease is expected need to be
identified for appropriately more aggressive
treatment to reduce the related morbidity and
mortality. Clinical decisions regarding those
patients depends on clinical and pathological
criteria, these criteria are not very accurate,
making it a challenging task to stratify patients
with PTC for optimal treatment. This fact paved
the road to the world of molecular biology and
the use of molecular markers. BRAF V600E
mutation is the most common mutation in PTC,
and has emerged as a promising molecular
marker for better prognostication and risk
stratification [28,31].
The BRAF V600E mutation is specific for PTC, is
not seen in benign tumors, is uncommon in
follicular thyroid cancer (<1.4%), and is not
frequently seen in Hurtle and medullary
thyroid carcinomas, but it was detected in the
anaplastic
thyroid
carcinoma
(10%)
[8,13,32,33].
Interestingly, the prevalence of BRAF mutation
was found to be associated with the geographic
area with a significantly higher prevalence in
Asia, especially Korea where the prevalence of
BRAF mutation reaches 83%, and lower
prevalence in the west [6,24]. Although the
mechanisms underlying this difference in BRAF
mutation frequencies are not well understood,
a recent theory suggested that these differences
might be associated with higher iodine intake
in Asian populations.
Furthermore,
Hashimoto's
thyroiditis
is
strongly associated with the development of
PTC. Because the prevalence of Hashimoto's
thyroiditis is higher in Korea, this positive
correlation may provide an explanation for the
higher incidence of PTC in this country [6].
While geographic differences in the incidence
of BRAF mutations are well established, the
association between age and BRAF mutation is
still controversial. Most of the studies denied
the presence of significant association, while
some studies reported that BRAF mutation was
associated with older age and they stated that it
is one of the reasons behind the worse
prognosis of PTC in the elder patients, and few
studies found an inverse relationship between
age and the BRAF mutation. As a matter of fact,
BRAF V600E mutation is very uncommon in
childhood PTC [34].
Most of the studies reported no significant
difference according to gender. Except for a few
studies that found higher prevalence of BRAF
mutations in males correlated with worsened
prognosis of PTC [20,23].
43(4 )2016 www.diclemedj.org 574
example, lymph node metastasis, advanced
stage and recurrence are more common in tall
than classic variant, and much less common in
the follicular variant [21,36].
Moreover, most of the anaplastic thyroid
cancers and the poorly differentiated tumors
that were BRAF-positive were found to have
adjacent areas of tall-cell variant PTC. These
findings provide evidence for the association
between this mutation and aggressive tumor
course which makes it a potentially important
marker for tumor diagnosis and prognosis and
for directing a more appropriate treatment
[13].
Death in PTC is strongly linked to disease
recurrence. Most tumor recurrences occur in
the thyroid site, para-tracheal and cervical
areas. There are many studies that correlate the
association between recurrence and the BRAF
mutation. Most of the studies demonstrated
higher risk of recurrence in patients with BRAF
mutation even after adjustment for other
factors that worsen the prognosis [21]. In
addition to that, BRAF-positive tumors are
more likely to be less differentiated with poor
response to radioiodine treatment, and it was
observed that the uptake of
131I was absent in
the majority of BRAF-positive tumors [18].
Interestingly, BRAF mutation was found to be
more common in recurrent tumors, which
reveals that this is the major mutation in
recurrent PTC [29-30].
CONCLUSIONS
BRAF mutation is the most common mutation
in PTC with higher prevalence in the eastern
countries of the world. It is a potentially useful
molecular marker, and may have a role in the
risk stratification, prognosis and treatment of
PTC. More studies should be done in order to
confirm its benefits for the diagnosis, treatment
and surveillance of PTC.
Declaration of Conflicting Interests:
The
authors declare that they have no conflict of
interest.
Financial Disclosure:
No financial support
was received.
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